The proposed research will determine the role of cytoplasmic polyadenylation element binding protein (CPEB) in mediating mRNA translational control during physiological and pathological neuronal function. The results will have implications for normal neuronal development and developmental dysregulation, as well as pathological processes in aging. CPEB has been recently implicated in models of learning and memory and we have evidence suggesting that CPEB may mediate both neuronal differentiation and neuron apoptosis. The cellular mechanisms underlying CPEB function in the brain are largely unknown but appear to be dependent upon NMDA receptor-stimulated activation of Aurora kinase and calcium influx. We will take advantage of the experimentally malleable PC12 cell model system and our experience in CPEB-directed regulation of mRNA translation in oocytes to explore these mechanisms. Findings in the PC12 cell system will be tested in cultured hippocampal neurons - a model which more closely mimics conditions found in the brain. First, we will define the role and mechanism of CPEB-directed mRNA translational control in the neuro-stimulatory action of nerve growth factor (NGF, PC12 cells ) and N-methyl-D-aspartate (NMDA, hippocampal neurons) and in cell cycle control and apoptosis. We will next characterize the signal transduction pathways that regulate CPEB function. The calcium-dependent CPEB signaling mechanisms may include the cAMP-dependent protein kinase (PKA), the calcium/calmodulin-dependent protein kinase II (CaMKII) or the mitogen-activated protein kinase (MAPK). These studies in PC12 cells and hippocampal neurons will lead to an understanding of the mechanisms of CPEB-mediated mRNA translation. Lastly, we will determine the CPEB isoform distribution in aging and Alzheimer's Disease (AD) postmortem human brain tissue. Three new isoforms of CPEB have been recently identified in the mouse brain which have sequences suggesting they are differentially regulated. The study of these processes in postmortem tissue will allow us to determine their clinical relevance and to identify potential therapeutic avenues in a number of pathological conditions.